Antecedent hematological disorders include the disorders myelofibrosis, aplastic anemia, paroxysmal nocturnal hemoglobinuria, polycythemia vera, and most commonly myelodysplastic syndrome. Myelodysplastic syndrome (MDS) refers to hematological conditions characterized by abnormalities in the production of one or more of the cellular components of blood (red cells, white cells (other than lymphocytes) and platelets (or their progenitor cells, megakaryocytes). MDS possesses a variable risk of progression to acute leukemia, resulting from ineffective blood cell production. The Merck Manual 953 (17th ed. 1999) and List et al., 1990, J. Clin. Oncol. 8:1424. Myelodysplastic syndromes (MDS) may be classified into several subtypes according to various systems of classification.
According to the French-American-British classification system, MDS may be classified according to the respective percentages of peripheral blasts and bone marrow blasts of the patient. See e.g., Bennett et al., Br. J. Haematol. 51:189-199 (1982); and Bennett et al., Br. J. Haematol. 87:746-754 (1994). Patients with MDS are classified as having one of five subtypes of disease: refractory anemia (RA); RA with ringed sideroblasts (RARS); RA with excess of blasts (RAEB); RAEB in transformation (RAEB-T); and chronic myelomonocytic leukemia (CMML). Myelodysplastic syndromes are generally indolent, with patients' blood counts remaining relatively stable over at least several months. With a moderate degree of variability, RAEB patients (those with 5% to 20% marrow blasts) and those with RAEB-T (20% to 30% marrow blasts) generally have a relatively poor prognosis, with a median survival ranging from 5 to 12 months. In contrast, RA patients (fewer than 5% blasts) or RARS patients (fewer than 5% blasts plus more than 15% ringed sideroblasts) have a median survival of approximately 3 to 6 years. The proportion of these individuals whose disease transforms to AML ranges from 5% to 15% in the low-risk RA/RARS group to 40% to 50% in the relatively high-risk RAEB/RAEB-T group. The FAB classification categorizes patients with more than 30% marrow blasts as having AML.
The subtype CMML can have 5-20% bone marrow blasts with a monocytosis of 1000/dL or more. It may be associated with splenomegaly. This subtype overlaps with a myeloproliferative disorder and may have an intermediate clinical course. It is differentiated from the classic chronic myelocytic leukemia (CML) that is characterized by a negative Ph chromosome.
MDS can also be classified according to the World Health Organization's (WHO) proposed system of classification. See, e.g. Brunning et al., Pathology and Genetics of Haematopoietic and Lymphoid Tissues, Lyon: IARC Press: 61-73 (2001); Harris et al., J. Clin. Oncol. 17:3835-3849 (1999); and Vardiman et al., Blood 100:2292-2302 (2002). MDS can be categorized under the WHO classification system according to the following criteria:
Refractory anemia (RA) is characterized by anemia with no or few blasts in the blood, and bone marrow displaying erythroid dysplasia only, less than 5% blasts, and less than 15% ringed sideroblasts.
Refractory cytopenia with multilineage dysplasia (RCMD) is characterized by cytopenias with no or few blasts in the blood, and bone marrow displaying dysplasia in greater than at least 10% of cells in at least 2 myeloid cell lines, less than 5% blasts, at least 15% ringed sideroblasts, and no Auer rods.
Refractory anemia with ringed sideroblasts (RARS) is characterized by anemia with no or rare blasts in the blood, and bone marrow displaying erythroid dysplasia only, less than 5% blasts, and at least 15% ringed sideroblasts.
Refractory cytopenia with multilineage dysplasia and ringed sideroblasts (RCMD-RS) is characterized by cytopenias with no or few blasts in the blood, and bone marrow displaying dysplasia at least 10% of cells in at least two myeloid cell lines, less than 5% blasts, no Auer rods, and at least 15% ringed sideroblasts.
Refractory anemia with excess blasts-1 (RAEB-1) is characterized by cytopenias with less than 5% blasts in the blood with no Auer rods, and bone marrow displaying unilineage or multilineage dysplasia, 5% to 9% blasts, and no Auer rods.
Refractory anemia with excess blasts-2 (RAEB-2) is characterized by cytopenias with between 5-19% blasts in the blood, and bone marrow displaying unilineage or multilineage dysplasia, and 10% to 19% blasts.
Myelodysplastic Syndrome, unclassified (MDS-U), is characterized by cytopenias with no or rare blasts in the blood and no Auer rods, and bone marrow displaying unilineage dysplasia in granulocytes or megakaryocytes, less than 5% blasts, and no Auer rods.
MDS associated with isolated del (5q) is characterized by anemia with less than 5% blasts in blood with normal or increased platelets, and bone marrow displaying normal or increased megakaryocytes with hypoloblated nuclei, less than 5% blasts, no Auer rods, and an isolated 5q31-33 chromosomal deletion.
MDS can also be classified according to the International Prognostic Scoring System. See, e.g. Greenberg et al., Blood 89:2079-2088 (1997); and Greenberg et al., Blood 91:1100 (1998). Under IPSS scoring, prognostic values are assigned to 3 categories: (1) percent marrow blasts (less than 5%=0; 5-10%=0.5; 11-20%=1.0; and 21-30%=2.0); (2) karyotype (normal cytogenetics=0; some chromosomal defects=0.5; complex, or chromosome 7 anomalies=1.5); and (3) cytopenia (a score of 0 if one of the following criteria are met: neutrophil count<1,800/mcL, platelets<100,000/mcL, Hb<10 g/dL; a score of 0.5 if two of three criteria are met). Risk is then determined based on the cumulative score of the 3 categories: “low” risk of MDS for an overall score of 0; “INT-1” risk of MDS for a score of 0.5-1; “INT-2” risk of MDS for an overall score of 1.5-2.0; and “high” risk of MDS for an overall score of 2.5 or higher.
The most common cases of MDS are primary, or idiopathic. However, a nonspecific history of exposure to indeterminable chemicals or radiation 10-15 years prior to onset of disease may be present in about 50% of patients. This relationship to pathogenesis remains unproved. Compounds such as, but not limited to, benzene, insecticides, weed killers, and fungicides are possible causes of MDS. Goldberg H., et al., Cancer Res. 1990 Nov. 1; 50(21): 6876-81. Secondary MDS describes development of MDS or acute leukemia after known exposures to chemotherapy drugs that can cause bone marrow damage. These drugs are associated with a high incidence of chromosomal abnormalities following exposure and at the time of MDS or acute leukemia diagnosis.
Further, MDS is associated with complications associated with severe cytopenias. Other complications are development of myelofibrosis, which can accelerate decline in blood counts and increase transfusion requirements. Transformation to acute leukemia accelerates the development of complications such as anemia, bleeding, and infections.
MDS Treatments
The current treatment of MDS is based on the stage and the mechanism of the disease that predominates the particular phase of the disease process. Bone marrow transplantation has been used in patients with poor prognosis or late-stage MDS. Epstein and Slease, 1985, Surg. Ann. 17:125. This type of therapy, however, is both painful for donor and recipient, because of the involvement of invasive procedures and can cause severe and even fatal complications to the recipient, particularly with allogeneic transplant and related Graft Versus Host Disease (GvHD) results. Therefore, the risk of GvHD restricts the use of bone marrow transplantation to patients with otherwise fatal diseases. Further, as most patients are elderly and only a few young MDS patients will have a matched donor, the use of bone marrow transplantation is limited.
An alternative approach to therapy for MDS is the use of hematopoietic growth factors or cytokines to stimulate blood cell development in a recipient. Dexter, 1987, J. Cell Sci. 88:1; Moore, 1991, Annu. Rev. Immunol. 9:159; and Besa E. C., Med. Clin. North Amer. 1992 May, 76(3): 599-617. The process of blood cell formation, by which a small number of self-renewing stem cells give rise to lineage specific progenitor cells that subsequently undergo proliferation and differentiation to produce the mature circulating blood cells has been shown to be at least in part regulated by specific hormones. These hormones are collectively known as hematopoietic growth factors. Metcalf, 1985, Science 229:16; Dexter, 1987, J. Cell Sci. 88:1; Golde and Gasson, 1988, Scientific American, July: 62; Tabbara and Robinson, 1991, Anti-Cancer Res. 11:81; Ogawa, 1989, Environ. Health Presp. 80:199; and Dexter, 1989, Br. Med. Bull. 45:337. The most well characterized growth factors include erythropoietin (EPO), granulocyte macrophage colony stimulating factor (GM-CSF), and granulocyte colony stimulating factor (G-CSF). Apart from inducing proliferation and differentiation of hematopoietic progenitor cells, such cytokines have also been shown to activate a number of functions of mature blood cells, including influencing the migration of mature hematopoietic cells. Stanley et al., 1976, J. Exp. Med. 143:631; Schrader et al., 1981, Proc. Natl. Acad. Sci. U.S.A. 78:323; Moore et al., 1980, J. Immunol. 125:1302; Kurland et al., 1979, Proc. Natl. Acad. Sci. U.S.A. 76:2326; Handman and Burgess, 1979, J. Immunol. 122:1134; Vadas et al., 1983, Blood 61:1232; Vadas et al., 1983, J. Immunol. 130:795; and Weibart et al., 1986, J. Immunol. 137:3584.
Unfortunately, hematopoietic growth factors have not proven effective in many clinical settings. Clinical trials of MDS patients treated with recombinant human GM-CSF and G-CSF have shown that while these cytokines can restore granulocytopoiesis in treated patients, their efficacy is restricted to the granulocyte or monocyte lineage with little or no improvement in hemoglobin or platelet counts. Schuster et al., 1990, Blood 76 (Suppl. 1):318a. When such patients were treated with recombinant human EPO, a sustained improvement in hemoglobin or decrease in transfusion requirement was achieved in only less than 25% of patients. Besa et al., 1990, Blood, 76 (Suppl. 1):133a; Hellstrom et al., 1990, Blood, 76 (Suppl. 1):279a; Bowen et al., 1991, Br. J. Haematol. 77:419.
Therefore, there remains a need for safe and effective methods of treating and managing antecedent hematological disorders, including MDS.